Protein Kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins. The phosphorylation of proteins modulates various cell activities such as cell growth, differentiation and proliferation. Abnormal PK activity has been related to a host of disorders, ranging from conditions such as psorisasis to life-threatening diseases such as glioblastoma (brain cancer).
A great deal of effort has been expended in attempts to identify ways of modulating PK activity. Examples include: biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Pat. No. 4,966,849); soluble receptors and antibodies (WO 94/10202, Kendall et al., Proc. Nat'l Acad. Sci., 90: 10705–09 (1994), Kim et al., Nature, 362: 841–844 (1993)); RNA ligands (Jelinek et al., Biochemistry, 33: 10450–56); Takano et al., Mol. Bio. Cell, 4: 358A (1993); Kinsella et al., Exo. Cell Res., 199: 56–62 (1992); Wright et al., J. Cellular Phys., 152: 448–57); and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani et al., Proc. Am. Assoc. Cancer Res., 35: 2268 (1994)). Despite such attempts, a need still exists for effective methods of modulating PK activity.